While much is now known about the acquisition and early natural history of HPV infections in sexually active young women, little is known about HPV infections in mid-adult women. In particular, the risk of acquiring new high-risk (HR) HPV infections from new sex partners is undefined and the frequency of reactivating HR HPV infections that were acquired in adolescence or young adulthood is unknown. Furthermore, the risk of abnormal cytology associated with new versus reactivated infections is undefined. We will enroll 1,000 women between the ages of 30 to 50 who are faculty, staff, or students at the University of Washington andfollow them with bi-annual clinical visits for two years. At each visit, a nurse practitioner will conduct a faceto-face medical and sexual behavior interview (supplemented with bi-weekly online sexual behavior diaries) and collect cervical specimens for Pap testing and for HPV genotyping and viral load testing. Serum for HPV antibody testing will be collected at the enrollment and exit visits. Women will also self-collect vaginal samples for HPV DNA testing at each visit, and a subset of 200 women will be selected to do monthly selfcollections between the month 6 and month 12 visits. The specific aims of this longitudinal study are to 1) define rates and determinants of newly acquired and reactivated type-specific HR HPV infections in midadult women;2) define the probability and determinants of reactivation in a subset of 200 women (with serologic evidence of prior infection and no recent new sex partners) followed with monthly vaginal selfcollections for HPV testing for 6 months;and 3) compare the probability of abnormal cytology (atypical squamous cells of undetermined significance or greater [ASC-US+]) associated with newly acquired versus re-activated type-specific HR HPV infections. Findings from this project will inform clinician/patient interactions and development of prophylactic vaccine implementation and cervical cancer screening guidelines in populations of mid-adult women.